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Transcriptional regulation of ataxia-telangiectasia and Rad3-related protein by activated p21-activated kinase-1 protects keratinocytes in UV-B-induced premalignant skin lesions
Published in Nature Publishing Group
2017
PMID: 28692051
Volume: 36
   
Issue: 44
Pages: 6154 - 6163
Abstract
Sun-induced skin lesions, in particular actinic keratosis, are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) and invasive SCC if left untreated. Therefore, understanding the molecular mechanisms by which the ultraviolet-B (UV-B)-exposed cells are being protected and the signaling pathways that promote the progression of certain premalignant skin lesions to malignant lesions will permit us to prevent or cure skin cancers. In the current study, we found that phospho-p21-activated kinase-1 (Pak1) and Pak1 expression was high in clinical samples of sunlight-induced premalignant skin lesions assessed by immunohistochemistry. Further, we observed that phospho-Pak1 and Pak1 levels are high in UV-B-exposed hairless SKH mouse model skin samples as compared with unexposed skin tissue. Our results from cell line and animal models showed that Pak1 is activated in response to UV-B radiation, and this activated Pak1 translocates from the cytoplasm to the nucleus. Inside the nucleus, Pak1 via C-Fos binds to a specific promoter region of DNA repair kinase ATR (ataxia-telangiectasia and Rad3-related protein) and acts as a transcriptional regulator of ATR. Results from our analysis showed that Pak1 overexpression, knockdown and Pak1 knockout cell line models showed that Pak1 confers protection to keratinocytes from UV-B-induced apoptosis and DNA damage via ATR. To our knowledge, this is the first study that evaluates the functional and clinical significance of a signaling molecule, Pak1, in sun-induced premalignant skin lesions and indicates that increased Pak1 activation and expression could serve as an early warning sign of progression toward non-melanoma skin cancer, if ignored.
About the journal
JournalOncogene
PublisherNature Publishing Group
ISSN09509232
Open AccessNo
Concepts (82)
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    Alkaline phosphatase
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    ATR PROTEIN
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    Messenger rna
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    NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE
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    P21 activated kinase 1
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    PAXILLIN
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    PROTEIN C FOS
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    Short hairpin rna
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    Tubulin
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    ATM PROTEIN
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    ATR PROTEIN, HUMAN
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    P21 ACTIVATED KINASE
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    PAK1 PROTEIN, HUMAN
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    A-431 cell line
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    Animal cell
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    Animal experiment
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    Animal model
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    Animal tissue
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    Apoptosis
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    Article
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    CANCER GROWTH
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    Cell nucleus
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    Cell protection
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    Cellular distribution
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    Controlled study
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    Cytoplasm
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    Dna damage
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    DNA DAMAGE RESPONSE
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    Dna repair
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    Gene activation
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    Gene silencing
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    HACAT CELL LINE
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    Hek293 cell line
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    Human
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    Human cell
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    Immunohistochemistry
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    In vitro study
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    Keratinocyte
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    Mouse
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    NON MELANOMA SKIN CANCER
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    Nonhuman
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    Precancer
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    Priority journal
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    Promoter region
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    Protein binding
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    Protein expression
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    Protein localization
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    Protein transport
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    SKIN DEFECT
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    SKIN PROTECTION
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    SUN EXPOSURE
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    Sunlight
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    Transcription initiation site
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    Transcription regulation
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    ULTRAVIOLET B RADIATION
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    Animal
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    Disease model
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    Gene expression regulation
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    Genetics
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    Metabolism
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    Pathology
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    RADIATION INDUCED NEOPLASM
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    Radiation response
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    Skin
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    Skin tumor
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    Squamous cell carcinoma
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    Tumor cell line
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    Ultraviolet radiation
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    Animals
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    ATAXIA TELANGIECTASIA MUTATED PROTEINS
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    CARCINOMA, SQUAMOUS CELL
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    Cell line, tumor
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    Disease models, animal
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    GENE EXPRESSION REGULATION, NEOPLASTIC
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    Humans
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    Keratinocytes
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    Mice
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    Neoplasms, radiation-induced
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    P21-ACTIVATED KINASES
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    PRECANCEROUS CONDITIONS
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    Skin neoplasms
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    Ultraviolet rays